Diabetes mellitus

1
Diabetes mellitus

• McMaster Mini-Med School
• March 17, 2004
• Dr. William Harper
• Assistant Professor of Medicine, McMaster
  University.
• Endocrinologist, Hamilton General Hospital
• www.drharper.ca

2
Diabetes Mellitus

• Type 1, IDDM, Juvenile-onset
• Type 2, NIDDM, Adult-onset

The pancreas!
3
(No Transcript)
4
Type 1 v.s. Type 2 Diabetes
Type 1 DM (lt 10) Type 2 DM (gt 90)
Age of onset lt 40 gt 40
DKA Yes No
Weight Usually lean 80 overweight
Cause Autoimmune or unknown No autoimmune markers
5
Pathophysiology of T1DM
antibodies attack islets!
6
Pathophysiology of T2DM
_
Hepatic glucose output
INSULIN

Blood glucose
Peripheral Tissue Uptake
diet
7
Natural History of Type 2 Diabetes
Insulin
resistance
Glucose
level
Insulin
production
b
-cell
dysfunction
Time
Normal
Impaired glucose
Type 2 diabetes
tolerance
8
Rising DM Prevalence (Diagnosed)
5.4
4.2
4.0
4.9
3.5
3.3
5.9
6.2
7.6
(Decimal Numbers Percent of the population
affected)
9
Why is the prevalence of Type 2 Diabetes mellitus
increasing?
10
The answer is magically ridiculous
11
Summary Public Health Impact

• DM Prevalence - 1/14 1/8 of age 40-75 1/5 of
  75
• - 1/3 unaware that they have DM
• - increasing throughout world
• IGT - age 40-49 12
• - age 50-59 14
• - age 60-74 21
• DM Risk in IGT - from epi studies 4 6/year
• DM Impact (USA) - 130B/yr (much of it ? CVD)

12
Diabetes Complications
Complications
Macrovascular
Microvascular
Diabetic eye disease (retinopathy and cataracts)
Stroke
Heart disease and hypertension 2-4 X increased
risk
Renal disease
Peripheral vascular disease
Erectile Dysfunction
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 199820(Suppl 8)S1-S29.
13
Disease Burden of Diabetes Mellitus

• Leading cause of blindness (12.5 of cases)
• Leading cause of ESRD (42 of cases)
• 50 of all non-traumatic amputations
• 2.5x increase risk of stroke
• 2-4x increase in cardiovascular mortality
• DM responsible for 25 of cardiac surgeries
• Mortality in DM 70 due to Cardiovascular disease

14
Haffner et al, NEJM, 339(4)229-34, 1998.
15
Is there any reason to be hopeful?
16
Is there any reason to be hopeful?YES!
17
Evans et al.

• BMJ 324 939-942
• April 2002
• Cross-sectional study
• DM 1155 patients
• MI 1347 patients
• Cohort study
• DM 3477 patients
• MI 7414 patients

18
(No Transcript)
19
Insulin Glargine (Lantus)
20
Insulin Glargine (Lantus)
21
Insulin
Type Starts Peaks Duration
Humalog NovoRapid 5-10 min 0.5-1hrs 3.5 hrs
Regular 30 min 2-4 hrs 6-8 hrs
NPH Lente 1-2 hrs 6-10 hrs 16-24 hrs
Ultralente 4-6 hrs 8-24 hrs 24-36 hrs
Glargine 1.5h None Up to 24 hrs
22
Sites of Action of Currently Available
Therapeutic Options
MUSCLE
ADIPOSE TISSUE
LIVER
PANCREAS
GLUCOSE PRODUCTION Metformin
Thiazolidinediones
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Metformin
INSULIN SECRETION Sulfonylureas
Glyburide, Gliclazide, Glimepiride Non-SU
Secretagogues Repaglinide, Nateglinide
INTESTINE
GLUCOSE ABSORPTION
Alpha-glucosidase inhibitors
23
Thiazolidinedione ß-cell preservation Animal
studies
12 weeks
16 weeks
Control Zucker Rats
ROSIG Zucker Rats
24
STENO-2, NEJM, 348383-93, 2003.
UKPDS 33, Lancet 352837-53, 1998.
DCCT, NEJM 329977-86, 1993.
25
Heart Protection Study
26
BP Trials in DM patients

• UKPDS
• atenolol captopril at reducing outcomes
• (UKPDS 39)
• Benefit to reducing SBP lt 120 (UKPDS 36, post-hoc
  subgroup analysis)
• Currently SBP target lt 120 being assessed in BP
  arm of the ACCORD Study

27
BP Trials in DM patients

• UKPDS atenolol captopril in ? events
• HOT felodipine, ? CV events with DBP lt 80
• ALLHAT
• Chlorthalidone gt lisinopril or amlodipine (less
  CHF)
• Chlorthalidone ? BS/diagnosis of DM
• LIFE (DM substudy)
• 1195 patients with DM/HTN/LVH
• Losartan gt atenolol in ? CV death/MI/CVA despite
  equivalent BP lowering effects
• HOPE not a BP trial per se

28
(No Transcript)
29
Effect of ACE Inhibitionin DiabetesHOPE Study
Complications

• Relative Risk Reduction of Ramipril vs. Placebo
  in Subjects with Diabetes
• 22 Myocardial infarction p 0.01
• 33 Stroke p 0.0074
• 37 Cardiovascular death p 0.0001
• 24 Overt nephropathy p 0.027
• 17 Revascularization p 0.031
• 20 Heart failure p 0.019

30
DM Nephropathy
Microalbuminuria 30-300 mg/d (20-200
ug/min) Macroalbuminuria gt 300 mg/d (gt 200
ug/min)
31
Smoking
32
(No Transcript)
33
Reducing risk in diabetes

• Glycemic control
• New insulins
• New oral agents
• CBG testing new sites (forearm), smarter
  monitors
• BP control
• ACE inhibitors
• Cholesterol control
• Aspirin
• Smoking cessation

34
(No Transcript)
35
Future

• Non-invasive BS testing
• Continuous BS monitor insulin pump
• Artificial Pancreas
• Islet cell transplants
• Stem-cell research
• Energy homeostasis breakthroughs

36
Cause for insulin resistance? Cause for Type 2
DM? Cause for obesity? An exercise pill?